Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy Journal Article
| Authors: | Pereira, P. M. R.; Sharma, S. K.; Carter, L. M.; Edwards, K. J.; Pourat, J.; Ragupathi, A.; Janjigian, Y. Y.; Durack, J. C.; Lewis, J. S. |
| Article Title: | Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy |
| Abstract: | Human epidermal growth factor receptor 2 (HER2) gene amplification and/or protein overexpression in tumors is a prerequisite for initiation of trastuzumab therapy. Although HER2 is a cell membrane receptor, differential rates of endocytosis and recycling engender a dynamic surface pool of HER2. Since trastuzumab must bind to the extracellular domain of HER2, a depressed HER2 surface pool hinders binding. Using in vivo biological models and cultures of fresh human tumors, we find that the caveolin-1 (CAV1) protein is involved in HER2 cell membrane dynamics within the context of receptor endocytosis. The translational significance of this finding is highlighted by our observation that temporal CAV1 depletion with lovastatin increases HER2 half-life and availability at the cell membrane resulting in improved trastuzumab binding and therapy against HER2-positive tumors. These data show the important role that CAV1 plays in the effectiveness of trastuzumab to target HER2-positive tumors. © 2018, The Author(s). |
| Keywords: | controlled study; human tissue; human cell; drug efficacy; nonhuman; mouse; animal tissue; gene; gene expression; protein depletion; epidermal growth factor receptor 2; animal experiment; animal model; protein; bladder cancer; amplification; cell membrane; cellular distribution; tumor; trastuzumab; endocytosis; drug binding; cell; chemical binding; membrane; caveolin 1; cell component; human; female; article; mcf-7 cell line; mda-mb-231 cell line; bladder tissue; bt-474 cell line; kato iii cell line; nci-n87 cell line; sk-br-3 cell line |
| Journal Title: | Nature Communications |
| Volume: | 9 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-12-03 |
| Start Page: | 5137 |
| Language: | English |
| DOI: | 10.1038/s41467-018-07608-w |
| PROVIDER: | scopus |
| PMCID: | PMC6277446 |
| PUBMED: | 30510281 |
| DOI/URL: | |
| Notes: | Nat. Commun. -- Export Date: 2 January 2019 -- Article -- Source: Scopus C7 - 5137 C2 - 30510281 |
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